Non-invasive methods to drive neural activity with millisecond precision and to recruit the brain's immune cells We recently discovered that flickering lights at gamma frequency (40 Hz) drives gamma frequency neural activity in visual cortex and recruits microglia to engulf pathogenic proteins in mouse models of Alzheimer's disease. However we do not yet know how to achieve these effects outside of visual cortex. If this sensory stimulation method could be adapted to non-invasively drive neural activity in deep brain regions this novel approach would enable new possible therapeutics for Alzheimer's and other neurological diseases. Our long- term goal is to harness these novel discoveries in order to manipulate neural activity and immune cells in humans. The goal of this proposal is to determine how to non-invasively drive temporally precise rhythmic neural activity in deep brain structures and to determine the effects of driving this activity on immune cells, synaptic plasticity, and neural codes essential for learning and memory in healthy mice and mouse models of Alzheimer's disease. In Aim 1 we will determine what types of sensory flicker produce the strongest rhythmic neural activity in deep brain structures. In Aim 2 we will establish the functional consequences of driving this non-invasive stimulation on microglia, connections between neurons, and neural codes essential for learning and memory. The rationale for this approach is that our discovery that millisecond precision sensory flicker stimulation drives rhythmic neural activity and recruits microglia provides the foundation for an innovative new method to non-invasively manipulate neural activity and immune cells. To achieve these aims, we will employ two key innovations. First, we will leverage our recent discovery showing that 40 Hz sensory stimulation drives gamma frequency activity and recruits microglia. Second, we will record neural activity in mice as they navigate a virtual reality environment to record neural activity from many cells of multiple types during behavior. The expected outcomes of these studies are novel non-invasive methods to drive neural activity, recruit immune cells, and alter synaptic plasticity and neural codes in deep brain structures. Because rhythmic brain activity and microglia are implicated in many neurological diseases and in learning and memory, these methods will spur new clinical and basic science research with wide-ranging impact. The novel approaches used in the study will be broadly distributed to drive further research on neural activity, immune cells, and neural-immune interactions.